The keto analog of L-leucine (a dietarily essential amino acid) is .alpha.-keto-isocaproic acid, which is usually referred to as ketoisocaproate (KIC), or sometimes also as ketoleucine. In the accepted description of leucine metabolism, leucine is first transaminated to its ketoacid, .sup..alpha. -ketoisocaproate (KIC). KIC then enters the mitochondria and is decarboxylated to isovalarylCoA by the branched chain ketoacid dehydrogenase. [See Krebs, et al., Adv. Enz. Reg. 15:375-394 (1976); and Paxton, et al., J. Biol. Chem. 257:14433-14439 (1982).] An alternate minor pathway has been described in the rat and human liver [Sabourn, et al., Fed. Proc. 38:283 (1979)]. This alternate oxidative pathway occurs in the cytosol and involves oxidation of KIC to .beta.-hydroxy-.beta.-methyl butyrate (HMB) by the enzyme KIC-oxygenase [Sabourn, et al., Arch. Biochem. Biophys. 206:132-144 (1981)].
The administration of keto analogs of amino acids has been proposed for treatment of certain disease conditions in humans, such as uremia. [See, for example, Walser, et al., J. Clin. Inv., 52:678-690 (1973).] For nutritional purposes, it is known that KIC is an inefficient substitute for leucine. Rat studies have shown that the feeding of KIC as a replacement for leucine requires the feeding of from two to three times as much KIC as the nutritionally required amount of leucine: Chawla, et al., J. Nutr., 105:798-803 (1975); and Boebel, et al., J. Nutr., 112: 1929-1939 (1982); and Chow, et al., J. Nutr., 104: 1208-1214 (1974).
It has been proposed to feed small amounts of KIC in conjunction with animal diets containing sufficient leucine for the purpose of improving the growth metabolism of the animals. By using milligram amounts of KIC, some increases in the rates of weight gain and/or feed efficiencies have been obtained. [See, for example, U.S. Pat. Nos. 4,760,090 and 4,883,817.] With mature sheep being fed for wool production, by feeding KIC the amount of wool produced may also be increased (U.S. Pat. No. 4,760,090). When lactating domestic animals, such as dairy cattle, are fed small amounts of KIC, the quantity of milk produced may be increased (U.S. Pat. No. 4,758,593). Egg production by laying chickens can also sometimes be increased (U.S. Pat. No. 4,760,531). Other effects of feeding KIC have been observed, including cholesterol reduction in meat, milk and eggs (U.S. Pat. Nos. 4,760,090 and 4,760,531). U.S. Pat. No. 4,835,185 describes the use of KIC as an immunomodulator for improving commercial performance of domestic animals. Specifically, the feeding of KIC is disclosed as a means for activating the blastogenesis function of the immune systems of the domestic animals, the KIC being administered in an amount enhancing blastogenesis of their T lymphocytes. It also disclosed that the administration of KIC will usually decrease plasma cortisol levels.